Ketterling, Rhett P.

Abstract Abstract 3315 The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(Tipifarnib), as maintenance therapy for acute myeloid leukemia (AML). Patients (pts) with AML in remission after requiring salvage therapy (primary induction failure or second or subsequent remission) or over the age of 60 in first remission were eligible. A confirmatory bone marrow exam was required within 2 weeks prior to randomization. Pts were eligible if they were in a complete remission (CR) or morphologic remission (MR). Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Adequate blood counts (absolute neutrophil count >= 1000/mm3 and platelet count >=50,000/mm3), and normal renal, and hepatic function were required within 2 weeks of randomization. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of this study was to compare disease free survival in the two groups. Although the study has completed accrual, an insufficient number of events have been recorded at this point to allow for evaluation of the survival data. However, toxicity data are now available. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). Seventy-three pts (51%) were male and 135 pts (94%) were white. Seventy-three pts were enrolled onto the treatment arm (Arm A) and 71 pts were enrolled onto the observation arm (Arm B). When the study was initially opened, pts on Arm A were treated with tipifarnib at a dose of 400 mg BID with dose reductions and interruptions defined per protocol for toxicity. After the first planned interim analysis, based on toxicity data, the ECOG Data Monitoring Committee recommended that the starting dose be decreased to 300 mg BID. The majority of pts enrolled on the study were in first CR (CR1) (Table 2). Among the 30 pts treated with the initial 400 mg BID dose, 23 pts (77%) had their dose held or reduced to a lower dose in the subsequent treatment cycles. For the 41 pts whose initial dose was 300 mg BID, 61% required either dose modification (n=19) or discontinued (n=6) due to toxicity. Table 1: Baseline characteristics Arm A 400 mg BID n=31 Arm A 300 mg BID n=42 Arm B Observation n=71 CR1 16 (52%) 34 (81%) 47 (66%) >CR1 10 (32%) 8 (19%) 16 (23%) Unknown 5 (16%) 16 (11%) Table 2: Toxicity Toxicity Type Arm A 400 mg n=31 Arm A 300 mg n=41 Arm B Observation n=69 Grade (n) Grade (n) Grade (n) 3 4 3 4 3 4 Hemoglobin 1 1 6 1 1 2 Leukocytes 2 4 16 4 3 Neutrophils 5 8 3 7 1 Platelets 4 10 11 11 1 5 Cardiac-ischemia 1 Fatigue 1 Diarrhea 1 Nausea 1 Febrile neutropenia 1 1 Infection w/gr 3-4 neutrophils (ANC) 1 Infection Gr0-2 ANC 1 1 3 GGT 1 Hypokalemia 1 Confusion 1 Agitation 1 Neuropathy-sensory 1 Back pain 1 Worst degree Non Hematologic 4 2 9 1 1 While non-hematologic toxicity was acceptable, significant hematologic toxicity was seen in pts treated at an initial dose of either 400 mg or 300 mg BID (Table 2). Of note, hematologic toxicity was also seen on the observation arm although less frequently than with both treatment doses. Non-hematologic toxicity was much less frequent overall and there were no significant non-hematologic toxicities in the observation arm. Reduction of the initial dose did not ameliorate either the hematologic or non-hematologic toxicity seen on the treatment arms. There was however no fatal toxicity at either dose level. Results of the randomization with respect to efficacy remain essential to determining the utility of this agent as maintenance therapy in AML. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 430 Background: The Dynamic International Prognostic Scoring System (DIPSS-plus) uses eight risk factors to predict overall survival (OS) in primary myelofibrosis (PMF): unfavorable karyotype, peripheral blood (PB) blast count ≥1%, platelet count <100 × 109/L, white blood cell count (WBC) >25 × 109/L, hemoglobin level <10 g/dL, red blood cell transfusion need, constitutional symptoms, and age >65 years (JCO 2011;29:392). Among these risk factors, karyotype holds a dominant role in predicting both overall (OS) and leukemia-free (LFS) survival (Blood 2011;118:4595). More recently, certain PMF-associated somatic mutations (IDH, EZH2, ASXL1, SRSF2) have been reported (in print or at recent meetings) to carry prognostic relevance for OS or LFS in PMF while other mutations (JAK2, MPL, TET2, SF3B1) did not. The purpose of the current study was to examine the individual and combined prognostic relevance of the former in the context of cytogenetic risk stratification and DIPSS-plus. Methods: An updated Mayo Clinic database of 1008 karyotypically- and DIPSS-plus-annotated patients with PMF was used to identify study patients in whom DNA at time of referral was available for mutation analysis. OS and LFS were calculated from the time of referral, which was also the time of study sample collection. Results: In an ongoing project, a total of 397 PMF patients have so far been studied for IDH1/2 (n=367), SRSF2 (n=355), ASXL1 (n=260) and EZH2 (n=43) mutations. The corresponding mutational frequencies were 5.4% (20/367), 14.4% (51/355), 31.2% (81/260) and 7% (3/43). These mutations were not exclusive of either each other or JAK2 or MPL mutations and a significant clustering was noted between SRSF2 and IDH mutations; IDH mutational frequency was 21% (10/48) in SRSF2-mutated versus 3% (9/279) in unmutated cases (P<0.0001). Mutational hotspots were P95 in exon 1 for SRSF2 and exons 1, 2 and 5 for ASXL1. OS and LFS effect have so far been examined for ASXL1, SRSF2 and IDH 1/2 mutations; in univariate analysis, all three mutations significantly affected OS (ASXL1 RR 1.9, 95% CI 1.4–2.7; SRSF2 RR 1.7, 95% CI 1.2–2.5; IDH 1/2 RR 1.8, 95% CI 1.1–3.1) whereas only IDH 1/2 (RR 5.5, 95% CI 2.5–11.8) and SRSF2 (RR 3.5, 95% CI 1.7–7.0) but not ASXL1 (p=0.29) mutations affected LFS. The observed prognostic relevance for OS was sustained during multivariable analysis that included ASXL1 with either SRSF2 or IDH mutations, as co-variates, whereas both IDH and SRSF2 mutations remained significant for LFS. Based on the above observations, study patients were classified into two groups: i) unmutated for ASXL1, SRSF2 and IDH1/2 (all unmutated; n=146) and ii) mutated for at least one of the three mutations (one or more mutated; n=130); the latter group constituted 62%, 52%, 18% and 27% of DIPSS-plus high, intermediate-2, intermediate-1and low risk patients, respectively (p<0.0001). The corresponding rates for patients with favorable and unfavorable karyotype were 47% and 43% (p=0.7) and for normal vs. abnormal karyotype were 53% and 36% (p=0.008). The “all unmutated group”, compared to the “one or more mutated group” enjoyed a significantly superior OS (RR 0.5, 95% CI 0.4–0.7) and LFS (RR 0.3, 95% CI 0.2–0.7) that was DIPSS-plus-independent for OS (p=0.03) and karyotype-independent for LFS (p=0.004). The prognostic value of distinguishing “all unmutated” from “one or more mutated” patient groups was most evident for DIPSS-plus intermediate-2 or lower risk groups (p=0.002) and its added value for high-risk group was limited (p=0.23) (Figure). Conclusions: A concomitant analysis strategy reveals that SRSF2, ASXL1 and IDH mutations carry inter-independent prognostic relevance for overall or leukemia-free survival in PMF. Any one of these three mutations is more likely to occur in patients with normal karyotype and such an event predicts shortened survival that is not accounted for by DIPSS-plus and a higher risk of leukemic transformation that is independent of karyotype. The current study suggests that such information might be useful in treatment decisions involving intermediate-2 or lower risk patients. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1875 Recent experimental evidence suggests that acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells (HSPC) following the acquisition of multiple genetic or epigenetic changes that initially give rise to pre-leukemic HSPC (pre-LSC) and then to fully transformed leukemia stem cells (LSC). Relapse continues to be the major cause of death in most subtypes of AML, suggesting that current therapies are largely ineffective in eliminating LSC and pre-LSC. Cellular heterogeneity and the recent observation that LSC are contained within different phenotypic cellular compartments are challenges for the identification of pathways contributing to the initiation and maintenance of AML. To address these challenges we employed a novel strategy of parallel transcriptional analysis of multiple phenotypic HSPC populations from individuals with AML with normal karyotype (N=5), -7/7q- (N=6) and complex karyotype (N=5), including long-term HSC, short-term HSC, and granulocyte-monocyte progenitors (GMP), and comparison to corresponding cell populations from age-matched healthy controls (HC) (N=6). Specifically, we sorted Lin−/CD34+/CD38−/CD90+ (LT-HSC), Lin−/CD34+/CD38−/CD90− (ST-HSC), and Lin−/CD34+/CD38+/CD123+/CD45RA+ (GMP), and hybridized RNA to Affymetrix GeneST 1.0 expression arrays. Differential gene expression was determined within each compartment by direct comparison of AML LT-HSC vs. HC LT-HSC, AML ST-HSC vs. HC ST-HSC, and AML GMP vs. HC GMP. Subsequent intersection of all differentially expressed genes revealed that only a relatively small number of 6 to 11 genes were consistently dysregulated in all examined leukemic stem and progenitor cell compartments. Interleukin 1 receptor accessory protein (IL1RAP) was one of the most significantly upregulated genes in LT-HSC, ST-HSC, and GMP in all examined subtypes of AML. IL1RAP is a transmembrane protein required for signaling through several receptors of the IL1 family, including IL-1R1 and ST2. We detected significant overexpression of IL1RAP protein on HSC and progenitor cells of AML patients. Interestingly, CD34+/Lin+ precursor cells showed only a marginal increase of IL1RAP at the protein level in AML, underscoring the importance of purifying HSPC with stringent lineage depletion. We performed fluorescence in situ hybridization in sorted IL1RAP+ and IL1RAP− cells from -7 AML. We observed that the -7 clone was restricted to IL1RAP+ cells, while IL1RAP- cells did not display monosomy 7, demonstrating that IL1RAP overexpression is a distinguishing feature of the cells of the -7 clone. Patients with normal karyotype AML showed a wider range of IL1RAP expression levels; some were as high as in -7 AML and others were as low as in HC. We asked whether IL1RAP expression levels were associated with known clinical or molecular parameters. We analyzed two published datasets of patients with normal karyotype AML (Metzeler, Blood. 2008;112:4193–4201; Tomasson, Blood. 2008;111:4797–4808). Patients with high IL1RAP levels showed inferior overall survival than patients with lower IL1RAP (p=2.2×10−7; median survival: 7.82 mo. for IL1RAP high, 20 mo. for IL1RAP low). Multivariate analysis using a Cox regression model showed that high IL1RAP status was an independent prognostic factor (p=0.002), and even stronger than FLT3 mutation status (p=0.006). In addition, we analyzed data from 183 patients with MDS and found IL1RAP expression to be specifically elevated in cases with RAEB-2, suggesting a role of IL1RAP in MDS and in the progression to AML. Downregulation of IL1RAP protein expression in 4 AML cell lines (THP1, OCI-AML3, HL60, HEL) led to a significant 45–98% decrease in clonogenic growth and increased apoptosis in vitro. To assess the effects of IL1RAP downregulation in vivo, we performed xenotransplants into immunodeficient NOD/SCID/IL2Rg-null mice. THP-1 AML cells showed a 92% reduced proliferation and infiltration of hematopoietic organs upon IL1RAP knockdown in comparison to a non-silencing control in vivo. Genetic studies to assess the role of IL1RAP in the initiation and maintenance of AML in an IL1RAP−/− mouse model are currently ongoing. In summary, our study provides a map of consistently dysregulated transcripts across multiple fractionated stem and progenitor cell types from patients with AML, and identifies IL1RAP as a putative new therapeutic and prognostic target in stem cells in AML and MDS. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 676 Although maintenance therapy has been shown to be of value in Acute Lymphoid Leukemia, its role in non M3 Acute Myeloid Leukemia (AML) has never been proven. Studies have been limited by issues related to efficacy as well as toxicity. The Eastern Cooperative Oncology Group (ECOG) trial, E2902, was a randomized phase III intergroup trial of the Farnesyl Transferase Inhibitor, R115777(tipifarnib), as maintenance therapy for AML. Patients(pts) with AML in remission after requiring salvage therapy or over age 60 in first remission were eligible. A confirmatory bone marrow exam prior to randomization was required to demonstrate a complete remission (CR) or morphologic remission(MR). Absolute neutrophil count >1000/mm3, platelet count >=50,000/mm3, normal renal, and hepatic function were required. Consolidation or post remission therapy prior to enrollment was allowed but not required. Pts who had received an allogeneic transplant in this remission were ineligible. Pts were randomized to either receive tipifarnib twice daily (BID) or to observation. The main objective of the study was to compare disease free survival (DFS) in the two groups. The study was designed with 84% power to detect a 76% relative increase in the median DFS from 3.4 months to 6 months (mo). The final analysis was to take place when 111 events had taken place. Between August 2004 and December 2009, 144 pts were accrued to the study. The median age of the pts is 70 (range 28–86). The majority of pts enrolled on the study (67%) were in first CR. Seventy three pts were enrolled onto the treatment arm and 71 pts were enrolled onto the observation arm. When the study initially opened, tipifarnib was given at a dose of 400 mg BID with dose reductions and interruptions as per protocol for toxicity. Based on the first interim analysis, toxicity data, the starting dose was decreased to 300 mg BID. Significant hematologic toxicity was seen in patients at both 300 and 400 mg. The majority of patients experienced >=grade 3 neutropenia or thrombocytopenia. There was 1 episode of febrile neutropenia. Non-hematologic toxicities were minimal. At the time of 110 events (90 relapses and 100 deaths), the final analysis of the study was conducted. The relapse rate was 60.3% on tipifarnib vs 64.8% for observation. Median DFS and 10 and 12 mo DFS and overall survival (OS) are documented in Table 1. Kaplan Meier curves for DFS and OS are presented. As the difference in median DFS is not considered significant (9.3 vs 5.8 mo, log rank p value 0.21), in July 2011, pts and physicians were informed of the lack of evidence of benefit so they could decide if they wished to continue drug. However an unplanned analysis of the data demonstrates a statistically significant improvement in OS at 10 months in pts who received tipifarnib. (70% vs 48%, p=0.05). While the benefit is subsequently lost, given a median survival measured in months, an increase in the number of pts alive and/or without disease at 10–12 mo is of value, particularly in the absence of noteworthy toxicity. Future studies are needed to better determine the role of maintenance therapy in pts with AML. Tipifarnib Observation Median DFS (months) 9.3 (95% CI:5.7, 13.3) 5.8 (95% CI: 3.7, 8.8) p=0.21 OS rate at 10 mo 70% (95% CI: 58%, 79%) 48% (95% CI: 36%, 60%) p=0.05 OS rate at 12 mo 59% (95% CI: 47%, 70%) 44% (95% CI: 32%, 55%) p=0.07 DFS rate at 10 mo 47% (95% CI: 36%, 59%) 32% (95% CI: 21%, 43%) p=0.07 DFS rate at 12 mo 39% (95% CI: 28%, 50%) 30% (95% CI: 20%, 41%) p=0.26 Disclosures: Larson: Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy; Ariad: Consultancy, Research Funding.

Abstract Abstract 423 Background: Cytogenetic abnormalities at diagnosis are seen in 20–70% of patients with myelodysplastic syndromes (MDS). The International Prognostic Scoring System -revised (IPSS-R) classifies these cytogenetic abnormalities into five prognostic groups: very good (del(11q), ΠY with overall survival (OS) of 61 months); good (normal, del(20q), del(5q), del(12p) with OS 49 months); intermediate (+8,7q-, i(17q),+19,+21 with OS 26 months); poor (der(3)q21/q26, −7, complex with 3 abnormalities with OS 16 months); and very poor (complex with >3 abnormalities with OS of 6 months) (Schanz J, JCO 2012, Greenberg P, Blood 2012). Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. We have previously shown that MK identifies a prognostically worse subgroup of MDS patients with a complex karyotype (Patnaik M, Leukemia 2010). Objectives: Methods: The Mayo Clinic database for MDS was used to identify patients in whom bone marrow histologic and cytogenetic information was obtained at the time of diagnosis. WHO criteria were used for MDS diagnosis and leukemic transformation. Results: i) Patient characteristics: A total of 1,014 patients met the above-stipulated criteria. Median age of the cohort was 71 years (range: 18–98 years) with 684 (67%) males. 819 patients (81%) had primary MDS with 195 cases (19%) of therapy-related MDS. 759 patients (75%) are dead at a median follow-up of 18 months (range: 0–223 months) with leukemic transformation documented in 125 cases (12%). IPSS-R risk distribution was as follows: very low (n=149, 15%), good (n=261, 26%), intermediate (n=221, 22%), high (n=131, 13%), and very high (n=252, 25%). ii) IPSS-R karyotype (Entire cohort; n=1,014): The five cytogenetic groups by IPSS-R were as follows: very good (n=43, 4%), good (n=577, 57%), intermediate (n=187, 18%), poor (n=83, 8%), and very poor (n=124, 12%). We evaluated the prognostic impact of the above groups by Kaplan Meier and Cox proportional hazards analysis. OS for the five cytogenetic groups was as follows: good (36 months), very good (28 months), intermediate (20 months), poor (13 months), and very poor (6 months) (Figure 1). OS of patients with very good karyotype was significantly better than patients with very poor and poor karyotype (p<0.0001, RR 3.2 and p=0.04, RR 1.6 respectively) but similar to patients with intermediate and good karyotype (p=0.22 and 0.28 respectively). iii) IPSS-R karyotype (Primary MDS; n=819): Cytogenetic risk groups by IPSS-R were as follows: very good (n=38, 5%), good (n=512, 63%), intermediate (n=153, 19%), poor (n=46, 6%), and very poor (n=70, 9%). OS of the five groups was as follows: good (39 months), very good (23 months), intermediate (21.5 months), poor (14.5 months), and very poor (6.5 months). OS of patients with very good karyotype was significantly better than patients with very poor karyotype (p=0.0002, RR 2.5) but similar to patients with poor, intermediate and good karyotype (p=0.23, 0.26 and 0.18 respectively). iv) Monosomal karyotype: MK was identified in 153 (15%) cases of which 4 cases were intermediate, 42 poor, and 107 very poor by IPSS-R. OS of patients with MK was similar to those with very poor karyotype (6 months). In addition, OS of patients with very poor without MK was akin to patients with poor without MK (p=0.21). Furthermore, among primary MDS we identified 83 (8%) cases of MK of which 4 were intermediate, 21 were poor, and 58 very poor by IPSS-R. We confirmed that OS of patients with MK was similar to patients with very poor karyotype (6.5 months). Moreover, survival of patients with very poor without MK was similar to patients with poor without MK (p=0.51). Conclusions: In this independent analysis of 1,014 patients with MDS, IPSS-R cytogenetic risk characterization failed to discriminate between very good, good and intermediate prognostic groups. In addition, patients with very poor without MK have a similar prognosis to patients with poor without MK and should be included in the poor category whereas the presence of MK should warrant inclusion into the very poor risk category. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 1802 Poster Board I-828 Background Heterogeneity in multiple myeloma (MM) leads to disparate outcomes with a wide variation in overall survival (OS). Based upon the evidence predominantly gathered from newly diagnosed patients treated with standard chemotherapy and/or transplantation, the current Mayo (mSMART) prognostic model uses a combination of metaphase cytogenetics, fluorescence in-situ hybridization (FISH) and plasma cell labeling index (PCLI) for risk-stratification at diagnosis of MM. The objective of our study was to evaluate the significance of this stratification model in the era of novel therapies, and to assess the independent prognostic value of each of the components in the model. Methods Data were abstracted from a cohort of 1556 consecutive patients with MM who presented to our institution between January 1999 and March 2009 within ninety days of diagnosis of MM A total of three hundred and eighty six patients had been evaluated with conventional cytogenetics near diagnosis in addition to interphase FISH. Out of this cohort, three hundred and sixty six patients had availability of all the three tests, including the slide-based PCLI. High-risk MM was defined as presence of any one or more of the following: cytogenetics: hypodiploidy, monosomy of chromosome 13 or deletion 13q ; FISH: deletion of p53 (locus 17p13) or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23); PCLI ≥3%. Survival estimates were created using the Kaplan-Meier method and compared by log-rank tests. The impact of each of the three tests was assessed by a multivariate (MV) analysis using Cox proportional hazards model. Results The median OS of the cohort of 366 patients was 65 months from presentation. One hundred and twelve (31%) patients were deemed high risk by any one or more of the three tests: Metaphase cytogenetics, FISH or PCLI (current mSMART definition of high-risk MM). The median OS of high risk patients was 52 months versus 71 months for standard-risk (P=0.007). We then studied the prognostic value of the three tests separately. Patients classified as high risk by FISH had a median OS of 35 months versus 65 months for the standard risk, HR= 2.3, P<0.001. Similarly, cytogenetics alone was also able to classify patients into high and standard risk with a comparable HR of 2.1 (P=0.008, median survival 37 vs. 64 months). In contrast, PCLI did not have a significant prognostic value (HR =1.41, P=0.32). This was confirmed on multivariate analysis in a model that included all 3 tests. FISH (HR=2.36, P=0.001) and cytogenetics (HR=1.99; P=0.017) emerged as independent determinants of prognosis in the multivariable analysis, while PCLI (HR=1.03, P=0.93) did not provide additional prognostic value. We then examined whether the prognostic value of FISH contributed additionally in patients classified into high and standard risk by conventional cytogenetics, and vice versa. Those classified as high risk by cytogenetics (n=44, 11 %), were further categorized into 2 groups by additional prognostic information obtained by FISH (median survival 18 vs. 52 months; P=0.005). Similarly, those classified as standard risk by cytogenetics (n=342, 89 %), were further categorized into 2 groups (median survival 52 vs. 71 months; P=0.017) by additional FISH-based stratification. Similarly, high-risk patients defined by FISH (n=65, 17 %) were further classified into 2 groups with significant difference in median OS (18 vs. 52 months, P=0.004), based on the presence or absence of high-risk features on cytogenetics. In contrast, no additional prognostic information was gained by cytogenetics in patients who were stratified as standard risk by FISH alone (n=321, 83%). Conclusion Our study validates high risk features defined by FISH and conventional cytogenetics in the mSMART risk stratification model among patients treated after the introduction of novel therapies. Either test identifies a high risk cohort with a hazard ratio of approximately 2 (median survival ∼37 versus ∼65 months). In patients known to have high risk disease by one of the two tests, knowledge of the other appears to add additional prognostic value. Disclosures Fonseca: Amgen, BMS, Celgene, Otsuka, Genzyme and Medtronic: Consultancy. Gertz:celgene, millennium: Honoraria. Dispenzieri:celgene: Research Funding. Kumar:celgene, genzyme, millennium, novartis, bayer: Research Funding; genzyme: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 3790 Background: Chronic myelomonocytic leukemia (CMML) is a clonal stem cell disorder characterized by: persistent peripheral blood (PB) monocytosis (>1 × 10(9)/L), absence of BCR-ABL1 fusion, absence of rearrangement of the PDGFRA/B genes, <20% bone marrow (BM) & PB blasts, and dysplasia involving one or more myeloid cell lines. It is clinically considered to be an overlapping syndrome with myelodysplastic and myeloproliferative features. The natural history and prognostic features of CMML are not well defined with the MD Anderson prognostic score (MDAPS) and the Spanish risk stratification by cytogenetics being the two major prognostic tools currently being used in clinical practice. Methods: 227 patients with WHO defined CMML were seen at the Mayo Clinic from 1997 through 2007. All patients underwent bone marrow (BM) examination and cytogenetic evaluation at diagnosis. We evaluated the prognostic relevance of several clinical and laboratory parameters including those previously identified by the MDAPS (Blood 2002;99:840) and the Spanish cytogenetic risk stratification (Haematologica 2011;96:375). Results: Among the 227 study patients, 153 (67%) were males and median age was 71 years (range, 17–90 years). There were 192 (85%) patients with CMML-1 & the remainder had CMML-2. At a median follow-up of 15 months, 166 (73%) deaths and 33 (14.5%) leukemic transformations were documented. Median survivals were 22 months for CMML-1 and 14 months for CMML-2. In univariate analysis, significant risk factors for survival included decreased hemoglobin level, decreased platelet count and increased levels of white blood cells (WBC), absolute neutrophils (ANC), absolute monocytes (AMC), absolute lymphocytes (ALC), PB blasts, BM blasts and presence of circulating immature myeloid cells (IMC; inclusive of PB blasts). However, on multivariable analysis that included the aforementioned Spanish cytogenetic risk stratification, only increased AMC (>10 × 10(9)/L, RR 2.5, 95% CI 1.7–3.8), presence of circulating IMC (RR 2.0, 95% CI 1.4–2.7), decreased hemoglobin (<10 g/dL; RR 1.6, 99% CI 1.2–2.2), and decreased platelet count (<100 × 10(9)/L; RR 1.4, 99% CI 1.0–1.9) retained significance. Using these four independent risk factors, we prepared a new prognostic risk model that performed better than both the MDAPS and the Spanish cytogenetic risk models (Figure). The Mayo risk model was also predictive of leukemic transformation: high risk RR 4.9 (95% CI 1.9–12.8) and intermediate risk RR 2.6 (1.1–5.9). Individual parameters of independent significance for leukemic transformation included PB blast count and AMC >10 × 10(9)/L. Conclusions: Absolute monocyte count is the strongest predictor of survival in CMML. Other independent risk factors include circulating immature myeloid cells, anemia and thrombocytopenia. A risk model based on these four risk factors is effective in predicting both overall and leukemia-free survival and outperforms both the MDAPS and risk stratification by cytogenetics. Disclosures: No relevant conflicts of interest to declare.

We report an index case of histiocytic sarcoma arising in a 70-year-old patient with long-standing chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The patient presented in 2017 with painful, enlarging swelling of the left neck. He had remote history of cutaneous squamous cell carcinoma with no sign of recurrence, and his CLL/SLL was thought to be in remission. Computed tomography showed mild splenomegaly and multifocal lymphadenopathy including a 3-cm left neck mass. Biopsy of the left neck mass showed CLL/SLL with associated histiocytic sarcoma. Flow cytometry demonstrated a B cell neoplasm with CLL/SLL phenotype. Despite radiation therapy, he expired 3 months after presentation. Two similar cases (CLL/SLL and histiocytic sarcoma, follicular lymphoma and Langerhans cell sarcoma) from another institution are also illustrated. The pathological features of combined tumors in lymphoid neoplasms, a general framework to the work-up to determine interrelatedness of tumor components, and the clinical relevance are discussed.

AimsThe aims of this study were to review our 5‐year experience with clinical FISH testing for TP63 rearrangements using both TP63 break‐apart (BAP) and TBL1XR1/TP63 dual‐fusion (D‐FISH) probes to evaluate the frequency of TP63 rearrangements and the distribution of TBL1XR1 vs. alternate partner loci, and to assess whether both probe sets are necessary in all cases undergoing FISH testing.Methods and resultsA retrospective review of the Mayo Clinic cytogenetic database identified 470 patients evaluated by FISH testing for TP63 rearrangements in formalin‐fixed paraffin‐embedded (FFPE) tissue using both BAP and D‐FISH probes. Of these, 25 (5.3%) had TP63 rearrangements. All samples were being investigated for anaplastic large‐cell lymphoma or other T cell lymphoma subtypes. A TBL1XR1 partner was identified by D‐FISH in 12 (48%) of 25 cases. All cases positive by TBL1XR1/TP63 D‐FISH were also positive by TP63 BAP FISH.ConclusionThis is the largest series of TP63 rearrangements to date. The frequency of positive results among cases referred to a large reference laboratory for TP63 FISH testing was 5.3%. Approximately half of TP63 rearrangements have a TBL1XR1 partner. TP63 BAP FISH testing is sufficient for up‐front testing of FFPE tissue samples. However, because of the genomic proximity of the TP63 and TBL1XR1 loci, we recommend reflex TBL1XR1/TP63 D‐FISH testing in positive and equivocal cases.

AbstractObjectivesMyeloid sarcoma with CBFB-MYH11 fusion may be enriched in abdominal sites. The clinicopathologic features of 11 cases are reported.MethodsWe collected clinical features, morphology, immunophenotype, and bone marrow (BM) involvement of myeloid sarcoma cases with CBFB-MYH11 fusion.ResultsEleven of 29 total myeloid sarcoma cases were CBFB-MYH11 positive and all 11 involved abdominal sites. The blastic infiltrate was associated with eosinophils in four of 11 cases and plasmacytoid dendritic cell (pDC) nodules in four of six cases. CD34, CD117, and myeloperoxidase were expressed in eight of nine, 10 of 10, and 10 of 10 cases, respectively. Ten of 10 cases showed no BM involvement.ConclusionsOur current series, combined with a literature review, identifies a compelling series of 31 (94%) of 33 cases of myeloid sarcoma with CBFB-MYH11 fusion showing a marked predilection for abdominal sites. In addition, the lack of obvious associated eosinophils, presence of pDC nodules, and lack of concurrent BM involvement suggest that “myeloid sarcoma with CBFB-MYH11 fusion” may represent a unique phenomenon.